Methods and Apparatus for Monopolar Renal Neuromodulation

ABSTRACT

Methods and apparatus are provided for monopolar neuromodulation, e.g., via a pulsed electric field. Such monopolar neuromodulation may effectuate irreversible electroporation or electrofusion, necrosis and/or inducement of apoptosis, alteration of gene expression, action potential attenuation or blockade, changes in cytokine up-regulation and other conditions in target neural fibers. In some embodiments, monopolar neuromodulation is applied to neural fibers that contribute to renal function. In some embodiments, such monopolar neuromodulation is performed bilaterally.

REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation-In-Part application ofco-pending United States Patent Application Nos.:

(a) U.S. patent application Ser. No. 11/129,765, filed on May 13, 2005,which claims the benefit of U.S. Provisional Application Nos.60/616,254, filed on Oct. 5, 2004; and 60/624,793, filed on Nov. 2,2004. Further, this application is a continuation-in-part of U.S. patentapplication Ser. No. 10/408,665, filed on Apr. 8, 2003 (published asUnited States Patent Publication 2003/0216792 on Nov. 20, 2003), whichclaims the benefit of U.S. Provisional Patent Application Nos.60/442,970, filed on Jan. 29, 2003; 60/415,575, filed on Oct. 3, 2002;and 60/370,190, filed on Apr. 8, 2002.

(b) U.S. patent application Ser. No. 11/189,563, filed on Jul. 25, 2005.

(c) U.S. patent application Ser. No. 11/266,933, filed on Nov. 4, 2005.

(d) U.S. patent application Ser. No. 11/363,867, filed on Feb. 27, 2006.

All of these applications, publications and patents are incorporatedherein by reference in their entireties.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and apparatus forneuromodulation. In some embodiments, the present invention relates tomethods and apparatus for achieving monopolar renal neuromodulation.

BACKGROUND

Congestive Heart Failure (“CHF”) is a condition that occurs when theheart becomes damaged and reduces blood flow to the organs of the body.If blood flow decreases sufficiently, kidney function becomes altered,which results in fluid retention, abnormal hormone secretions andincreased constriction of blood vessels. These results increase theworkload of the heart and further decrease the capacity of the heart topump blood through the kidneys and circulatory system.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.Moreover, the fluid overload and associated clinical symptoms resultingfrom these physiologic changes result in additional hospital admissions,poor quality of life and additional costs to the health care system.

In addition to their role in the progression of CHF, the kidneys play asignificant role in the progression of Chronic Renal Failure (“CRF”),End-Stage Renal Disease (“ESRD”), hypertension (pathologically highblood pressure) and other cardio-renal diseases. The functions of thekidneys can be summarized under three broad categories: filtering bloodand excreting waste products generated by the body's metabolism;regulating salt, water, electrolyte and acid-base balance; and secretinghormones to maintain vital organ blood flow. Without properlyfunctioning kidneys, a patient will suffer water retention, reducedurine flow and an accumulation of waste toxins in the blood and body.These conditions result from reduced renal function or renal failure(kidney failure) and are believed to increase the workload of the heart.In a CHF patient, renal failure will cause the heart to furtherdeteriorate as fluids are retained and blood toxins accumulate due tothe poorly functioning kidneys.

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. An increase in renal sympathetic nerve activity leads todecreased removal of water and sodium from the body, as well asincreased renin secretion. Increased renin secretion leads tovasoconstriction of blood vessels supplying the kidneys which causesdecreased renal blood flow. Reduction of sympathetic renal nerveactivity, e.g., via denervation, may reverse these processes.

Applicants have previously described methods and apparatus for treatingrenal disorders by applying a pulsed electric field to neural fibersthat contribute to renal function. See, for example, Applicants'co-pending U.S. patent application Ser. No. 11/129,765, filed on May 13,2005, and Ser. No. 11/189,563, filed on Jul. 25, 2005, both of which areincorporated herein by reference in their entireties. A pulsed electricfield (“PEF”) may initiate renal neuromodulation, e.g., denervation, forexample, via irreversible electroporation or via electrofusion. The PEFmay be delivered from apparatus positioned intravascularly,extravascularly, intra-to-extravascularly or a combination thereof.Additional methods and apparatus for achieving renal neuromodulation,e.g., via localized drug delivery (such as by a drug pump or infusioncatheter) or via use of a stimulation electric field, etc, aredescribed, for example, in co-owned and co-pending U.S. patentapplication Ser. No. 10/408,665, filed Apr. 8, 2003, and U.S. Pat. No.6,978,174, both of which are incorporated herein by reference in theirentireties.

Electrofusion generally refers to the fusion of neighboring cellsinduced by exposure to an electric field. Contact between targetneighboring cells for the purposes of electrofusion may be achieved in avariety of ways, including, for example, via dielectrophoresis. Intissue, the target cells may already be in contact, thus facilitatingelectrofusion.

Electroporation and electropermeabilization generally refer to methodsof manipulating the cell membrane or intracellular apparatus. Forexample, the porosity of a cell membrane may be increased by inducing asufficient voltage across the cell membrane through, e.g., short,high-voltage pulses. The extent of porosity in the cell membrane (e.g.,size and number of pores) and the duration of effect (e.g., temporary orpermanent) are a function of multiple variables, such as field strength,pulse width, duty cycle, electric field orientation, cell type or sizeand/or other parameters.

Cell membrane pores will generally close spontaneously upon terminationof relatively lower strength electric fields or relatively shorter pulsewidths (herein defined as “reversible electroporation”). However, eachcell or cell type has a critical threshold above which pores do notclose such that pore formation is no longer reversible; this result isdefined as “irreversible electroporation,” “irreversible breakdown” or“irreversible damage.” At this point, the cell membrane ruptures and/orirreversible chemical imbalances caused by the high porosity occur. Suchhigh porosity can be the result of a single large hole and/or aplurality of smaller holes.

A potential challenge of using intravascular PEF systems for treatingrenal disorders is to selectively electroporate target cells withoutaffecting other cells. For example, it may be desirable to irreversiblyelectroporate renal nerve cells that travel along or in proximity torenal vasculature, but it may not be desirable to damage the smoothmuscle cells of which the vasculature is composed. As a result, anoverly aggressive course of PEF therapy may persistently injure therenal vasculature, but an overly conservative course of PEF therapy maynot achieve the desired renal neuromodulation.

Applicants have previously described methods and apparatus formonitoring tissue impedance or conductivity to determine the effects ofpulsed electric field therapy, e.g., to determine an extent ofelectroporation and/or its degree of irreversibility. See, for example,Applicant's co-pending U.S. patent application Ser. No. 11/233,814,filed Sep. 23, 2005, which is incorporated herein by reference in itsentirety. Pulsed electric field electroporation of tissue causes adecrease in tissue impedance and an increase in tissue conductivity. Ifinduced electroporation is reversible, tissue impedance and conductivityshould approximate baseline levels upon cessation of the pulsed electricfield. However, if electroporation is irreversible, impedance andconductivity changes should persist after terminating the pulsedelectric field. Thus, monitoring the impedance or conductivity of targetand/or non-target tissue may be utilized to determine the onset ofelectroporation and to determine the type or extent of electroporation.Furthermore, monitoring data may be used in one or more manual orautomatic feedback loops to control the electroporation.

In view of the foregoing, it would be desirable to provide additionalmethods and apparatus for achieving renal neuromodulation.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the present invention will be apparent uponconsideration of the following detailed description, taken inconjunction with the accompanying drawings, in which like referencecharacters refer to like parts throughout, and in which:

FIG. 1 is a schematic view illustrating human renal anatomy.

FIG. 2 is a schematic isometric detail view showing the location of therenal nerves relative to the renal artery.

FIGS. 3A and 3B are schematic isometric and end views, respectively,illustrating orienting of an electric field for selectively affectingrenal nerves.

FIG. 4 is a schematic side view, partially in section, illustrating anexample of a monopolar extravascular method and apparatus for renalneuromodulation.

FIG. 5 is a schematic side view, partially in section, illustrating anexample of a monopolar intra-to-extravascular method and apparatus forrenal neuromodulation.

FIGS. 6A and 6B are schematic side views, partially in section,illustrating examples of monopolar intravascular methods and apparatusfor renal neuromodulation.

FIGS. 7A-7D are schematic side views, partially in section, illustratingexamples of monopolar intravascular methods and apparatus for renalneuromodulation comprising centering elements.

FIG. 8 is a schematic side view, partially in section, illustrating amethod for multi-location monopolar renal neuromodulation.

FIG. 9 is a schematic side view, partially in section, illustrating anexample of a monopolar intravascular method and apparatus for renalneuromodulation having one or more electrodes that contact the vesselwall.

FIG. 10 is a schematic side view, partially in section, illustratinganother example of a monopolar intravascular method and apparatus forrenal neuromodulation having one or more electrodes that contact thevessel wall

FIG. 11 is a schematic side view, partially in section, of a method forachieving monopolar bilateral renal neuromodulation, illustrativelyutilizing the apparatus of FIG. 6A.

FIG. 12 is a schematic side view, partially in section, illustrating analternative method and apparatus for achieving monopolar bilateral renalneuromodulation.

DETAILED DESCRIPTION A. Overview

Several embodiments of the present invention are methods and apparatusfor neuromodulation via a pulsed electric field (“PEF”), a stimulationelectric field, localized drug delivery, high frequency ultrasound,thermal techniques, athermal techniques, combinations thereof, and/orother techniques. In some embodiments, neuromodulation is achieved viamonopolar (e.g., unipolar) methods and apparatus. Such neuromodulationmay, for example, effectuate irreversible electroporation orelectrofusion, necrosis and/or inducement of apoptosis, alteration ofgene expression, action potential blockade or attenuation, changes incytokine up-regulation and other conditions in target neural fibers.

In some patients, when the monopolar neuromodulatory methods andapparatus of the present invention are applied to renal nerves and/orother neural fibers that contribute to renal neural functions,applicants believe that the neuromodulatory effects induced by theneuromodulation might result in increased urine output, decreased plasmarenin levels, decreased tissue (e.g., kidney) and/or urinecatecholamines (e.g., norepinephrine), increased urinary sodiumexcretion, and/or controlled blood pressure. Furthermore, applicantsbelieve that these or other changes might prevent or treat congestiveheart failure, hypertension, acute myocardial infarction, end-stagerenal disease, contrast nephropathy, other renal system diseases, and/orother renal or cardio-renal anomalies. The methods and apparatusdescribed herein may be used to modulate efferent or afferent nervesignals, as well as combinations of efferent and afferent nerve signals.

Renal neuromodulation preferably is performed in a bilateral fashionsuch that neural fibers contributing to renal function of both the rightand left kidneys are modulated. Bilateral monopolar renalneuromodulation may provide enhanced therapeutic effect in some patientsas compared to renal neuromodulation performed unilaterally, i.e. ascompared to renal neuromodulation performed on neural tissue innervatinga single kidney. In some embodiments, concurrent modulation of neuralfibers that contribute to both right and left renal function may beachieved, or in other embodiments modulation of the right and leftneural fibers may be sequential. Bilateral renal neuromodulation may becontinuous or intermittent, as desired.

When utilizing an electric field, the electric field parameters may bealtered and combined in any suitable combination. Such parameters caninclude, but are not limited to, voltage, field strength, frequency,pulse width, pulse duration, the shape of the pulse, the number ofpulses and/or the interval between pulses (e.g., duty cycle), etc. Forexample, when utilizing a pulsed electric field, suitable fieldstrengths can be up to about 10,000 V/cm and suitable pulse widths canbe up to about 1 second. Suitable shapes of the pulse waveform include,for example, AC waveforms, sinusoidal waves, cosine waves, combinationsof sine and cosine waves, DC waveforms, DC-shifted AC waveforms, RFwaveforms, square waves, trapezoidal waves, exponentially-decayingwaves, or combinations. The field includes at least one pulse, and inmany applications the field includes a plurality of pulses. Suitablepulse intervals include, for example, intervals less than about 10seconds. These parameters are provided as suitable examples and in noway should be considered limiting.

As discussed, the methods and apparatus of the present invention may beused to modulate neural fibers that contribute to renal function and mayexploit any suitable neuromodulatory techniques that will achieve thedesired neuromodulation. For example, any suitable electrical signal orfield parameters, such as any electric field that will achieve thedesired neuromodulation (e.g., electroporative effect), may be utilized.In some embodiments, the present invention provides methods andapparatus for achieving bilateral renal neuromodulation. To betterunderstand the structures of devices of the present invention and themethods of using such devices for renal neuromodulation, it isinstructive to examine the renal anatomy in humans.

B. Selected Embodiments of Methods for Neuromodulation

With reference now to FIG. 1, the human renal anatomy includes kidneys Kthat are supplied with oxygenated blood by renal arteries RA, which areconnected to the heart by the abdominal aorta AA. Deoxygenated bloodflows from the kidneys to the heart via renal veins RV and the inferiorvena cava IVC. FIG. 2 illustrates a portion of the renal anatomy ingreater detail. More specifically, the renal anatomy also includes renalnerves RN extending longitudinally along the lengthwise dimension L ofrenal artery RA generally within the adventitia of the artery. The renalartery RA has smooth muscle cells SMC that surround the arterialcircumference and spiral around the angular axis θ of the artery. Thesmooth muscle cells of the renal artery accordingly have a lengthwise orlonger dimension extending transverse (i.e., non-parallel) to thelengthwise dimension of the renal artery. The misalignment of thelengthwise dimensions of the renal nerves and the smooth muscle cells isdefined as “cellular misalignment.”

Referring to FIGS. 3A and 3B, the cellular misalignment of the renalnerves and the smooth muscle cells may be exploited to selectivelyaffect renal nerve cells with reduced effect on smooth muscle cells.More specifically, because larger cells require a lower electric fieldstrength to exceed the cell membrane irreversibility threshold voltageor energy for irreversible electroporation, embodiments of the presentinvention may be configured to align at least a portion of an electricfield with or near the longer dimensions of the cells to be affected. Inspecific embodiments, the device has a monopolar electrode configured tocreate an electrical field aligned with or near the lengthwise dimensionL of the renal artery RA to affect renal nerves RN. By aligning anelectric field so that the field preferentially aligns with thelengthwise aspect of the cell rather than the diametric or radial aspectof the cell, lower field strengths may be used to affect target neuralcells, e.g., to necrose or fuse the target cells, to induce apoptosis,to alter gene expression, to attenuate or block action potentials, tochange cytokine up-regulation and/or to induce other suitable processes.This is expected to reduce total energy delivered to the system and tomitigate effects on non-target cells in the electric field.

Similarly, the lengthwise or longer dimensions of tissues overlying orunderlying the target nerve are orthogonal or otherwise off-axis (e.g.,transverse) with respect to the longer dimensions of the nerve cells.Thus, in addition to aligning a pulsed electric field (“PEF”) with thelengthwise or longer dimensions of the target cells, the PEF maypropagate along the lateral or shorter dimensions of the non-targetcells (i.e., such that the PEF propagates at least partially out ofalignment with non-target smooth muscle cells SMC). Therefore, as seenin FIGS. 3A and 3B, applying a PEF with propagation lines Li generallyaligned with the longitudinal dimension L of the renal artery RA isexpected to preferentially cause electroporation (e.g., irreversibleelectroporation), electrofusion or other neuromodulation in cells of thetarget renal nerves RN without unduly affecting the non-target arterialsmooth muscle cells SMC. The pulsed electric field may propagate in asingle plane along the longitudinal axis of the renal artery, or maypropagate in the longitudinal direction along any angular segment θthrough a range of 0°-360°.

A PEF system placed within and/or in proximity to the wall of the renalartery may propagate an electric field having a longitudinal portionthat is aligned to run with the longitudinal dimension of the artery inthe region of the renal nerves RN and the smooth muscle cells SMC of thevessel wall so that the wall of the artery remains at leastsubstantially intact while the outer nerve cells are destroyed, fused orotherwise affected. Monitoring elements optionally may be utilized toassess an extent of, e.g., electroporation, induced in renal nervesand/or in smooth muscle cells, as well as to adjust PEF parameters toachieve a desired effect.

C. Embodiments of Systems and Methods for Neuromodulation

With reference to FIGS. 4-10, examples of monopolar PEF systems andmethods are described. FIG. 4 shows one embodiment of an extravascular,monopolar pulsed electric field apparatus 200 that includes one or moreelectrodes configured to deliver a monopolar pulsed electric field torenal neural fibers to achieve renal neuromodulation. The apparatus ofFIG. 4 is configured for temporary extravascular placement; however, itshould be understood that partially or completely implantableextravascular apparatus additionally or alternatively may be utilized.Applicants have previously described extravascular PEF systems, forexample, in co-pending U.S. patent application Ser. No. 11/189,563,filed Jul. 25, 2005, which has been incorporated herein by reference inits entirety.

Apparatus 200 of FIG. 4 comprises a laparoscopic or percutaneous PEFsystem having a probe 210 configured for insertion in proximity to thetrack of the renal neural supply. For example, the probe 210 can beconfigured to be placed along the renal artery or vein, the hilum,and/or within Gerota's fascia under CT, radiographic, ultrasonic, orother suitable guidance. The proximal section of the probe 210 generallyhas an electrical connector to couple the probe to a pulse generator100, and the distal section has at least one electrode 212.

The pulsed electric field generator 100 is located external to thepatient, and the electrode(s) 212 are electrically coupled to thegenerator via the probe 210 and wires 211. The generator 100, as well asany of the electrode embodiments described herein, may be utilized withany embodiment of the present invention described hereinafter fordelivery of a PEF with desired field parameters. It should be understoodthat electrodes of embodiments described hereinafter may beelectronically connected to the generator even if the generator is notexplicitly shown or described with each embodiment.

The electrode(s) 212 can be individual electrodes, a common butsegmented electrode, or a common and continuous electrode. A common butsegmented electrode may be formed by providing a slotted tube fittedonto the probe, or by electrically connecting a series of individualelectrodes. Individual electrodes or groups of electrodes 212 may beconfigured to provide a monopolar or bipolar signal. The electrodes 212may be dynamically assignable to facilitate monopolar and/or bipolarenergy delivery between/among any of the electrodes on the probe 210and/or an external ground pad 150. The ground pad 150, for example, maybe attached externally to the patient's skin (e.g., to the patient'sleg, flank, back or side). Additionally or alternatively, the ground pad150 may be attached externally to the patient adjacent to the targetedkidney to induce desired directionality in the monopolar electricalfield.

As seen in FIG. 4, the electrode 212 may comprise a single electrodethat is used in conjunction with a separate ground pad 150 located onthe exterior of the patient and coupled to the generator 100 formonopolar use. The probe 210 optionally may comprise a conductivematerial that is insulated in regions other than its distal tip to forma distal tip electrode 212. Alternatively, the electrode 212 may bedelivered through a lumen of the probe 210. The probe 210 and theelectrode 212 may be of the standard needle or trocar-type usedclinically for pulsed RF nerve block. Alternatively, the apparatus 200may comprise a flexible and/or custom-designed probe for the renalapplication described herein.

In FIG. 4, the percutaneous probe 210 has been advanced through apercutaneous access site P into proximity within renal artery RA. Onceproperly positioned, a pulsed electric field F₀ may be applied to targetneural fibers across the monopolar electrode 212 and the ground pad 150.The pulsed electric field F₀ shown in FIG. 4 is generally aligned withthe longitudinal dimension of the neural fibers along the renal arteryRA that control the kidney K to preferentially modulate the neuralfibers without unduly affecting the smooth muscle cells of the renalartery RA. The monopolar electric field F₀, however, can be orientateddifferently relative to the renal artery RA in other embodiments. Aftertreatment, the apparatus 200 may be removed from the patient to concludethe procedure.

It is expected that applying a monopolar field between the electrode 212and the ground pad 150 may modulate the function of the target neuralfibers in a manner that at least partially denervates the patient'skidney. The neural modulation may be achieved thermally or substantiallyathermally. Such PEF therapy may alleviate clinical symptoms of CHF,hypertension, renal disease, myocardial infarction, contrast nephropathyand/or other renal or cardio-renal diseases for a period of months(e.g., potentially up to six months or more). This time period may besufficient to allow the body to heal to potentially reduce the risk ofCHF onset after an acute myocardial infarction and mitigate the need forsubsequent re-treatment. Alternatively, as symptoms reoccur, or atregularly scheduled intervals, the patient can return to the physicianfor a repeat therapy.

The effectiveness of the initial therapy, and thus the potential needfor repeating the therapy, can be evaluated by monitoring severaldifferent physiologic parameters. For example, plasma renin levels,urine catecholamines, or other neurohormones that are indicative ofincreased sympathetic nervous activity can provide an indication of theextent of denervation. Additionally or alternatively, a nuclear imagingtest, such as a test utilizing 131-Iodine metaiodobenzylguanidine(“MIBG”), may be performed to measure a degree of adrenergicinnervation. As another option, imaging may be performed withTechnetium-99m mercaptoacetylglycine (“Tc-99m MAG3”) to evaluate renalfunction. Alternatively, provocative maneuvers known to increasesympathetic nervous activity, such as head-out water immersion testing,may be conducted to determine the need for repeat therapy.

In some embodiments, the apparatus 200 may comprise a probe having anintroducer with an expandable distal segment having one or moreelectrodes. After insertion in proximity to target neural fibers, thedistal segment may be opened or expanded into an expanded configuration.In one embodiment, this expanded configuration would follow a contour ofthe renal artery and/or vein to treat a number of neural fibers with asingle application of PEF therapy. For example, in the expandedconfiguration, the distal segment may partially or completely encirclethe renal artery and/or vein. In another embodiment, the expandedconfiguration may facilitate mechanical dissection, for example, toexpand Gerota's fascia and create a working space for placement of theelectrodes and/or for delivery of PEF therapy. The distal segmentoptionally may be translated independently of the probe or introducer.

When utilized as an electrode, the distal segment may, for example, beextended out of an introducer placed near the treatment area. Theconducting distal segment may be advanced out of the sheath until adesired amount of renal neural tissue is in proximity to the distalsegment, and then PEF therapy may be delivered via the distal segmentelectrode. Alternatively, the conducting distal segment may be allowedto reform or expand into a spiral of one or more loops, a randomspace-occupying shape, or another suitable configuration. Mesh, braid,or conductive gels or liquids could be employed in a similar manner.

FIG. 5 schematically illustrates a monopolar intra-to-extravascular(ITEV) PEF system 300 having electrode(s) that are initially deliveredendoluminally in a retracted configuration (not shown) to anintravascular position near target neural fibers for modulating renalfunction. The distal portions of the electrodes then piercethrough/across the vessel wall to an extravascular position prior todelivery of the PEF therapy. Intra-to-extravascular positioning of theelectrode(s) may place the electrode(s) in closer proximity to targetneural fibers during the PEF therapy compared to fully intravascularpositioning of the electrode(s). Applicants have previously describedintra-to-extravascular PEF systems, for example, in co-pending U.S.patent application Ser. No. 11/324,188, filed Dec. 29, 2005, which isincorporated herein by reference in its entirety.

The example of the monopolar ITEV PEF system 300 shown in FIG. 5comprises a catheter 310 having an expandable element 312 with one ormore needle-like ITEV electrodes 314 coupled to the expandable element.When multiple needle electrodes 314 are provided, they may be spacedcircumferentially and/or longitudinally about/along the expandableelement 312. The system 300 further comprises the previously describedground pad 150, which may be attached to or otherwise placed against theskin S of the patient along the exterior of the patient (e.g., to thepatient's flank, back, thigh or side). The ground pad 150 is alsocoupled to the PEF generator 100 as a return electrode (see FIG. 4). Theground pad 150 optionally may be positioned substantially directlylateral to the ITEV electrode(s) 314 to direct the PEF therapy along thepatient's vasculature (e.g., along renal artery RA).

The expandable element 312 comprises a member or structure configuredfor intravascular delivery to (and retrieval from) a target location ina low profile configuration and for expansion to an expanded deployedconfiguration at the target location. The expandable element 312 maycomprise, for example, an inflatable balloon, an expandable basket orcage, or some other expandable structure. As seen in FIG. 5, expansionof the expandable element 312 causes the ITEV electrode(s) 314 to piercethe wall of renal artery RA and move from an intravascular location toan extravascular location. With the ITEV electrode(s) 314 positionedextravascularly and coupled to the PEF generator 100, the ITEVelectrode(s) may be energized (e.g., one at a time or all together) asactive electrodes in a monopolar PEF therapy with the external groundpad 150 serving as the return electrode. Additionally or alternatively,bipolar PEF therapy may be delivered between any pair of the ITEVelectrodes 314 in conjunction with or in lieu of monopolar therapy.

With reference now to FIGS. 6A and 6B, in addition to monopolarextravascular and monopolar ITEV PEF systems, another example of theinvention is a monopolar intravascular PEF system 400. Applicants havepreviously described intravascular PEF systems, for example, inco-pending U.S. patent application Ser. No. 11/129,765, filed May 13,2005, which has been incorporated herein by reference in its entirety.

The monopolar intravascular PEF system 400 of FIG. 6A comprises acatheter 410 having a monopolar electrode 412 coupled to the shaft ofthe catheter. The catheter 410 comprises a guide wire lumen forendoluminally advancing the system 400 to a desired intravascularposition over a guide wire G (e.g., to a position within a patient'srenal artery RA). The electrode 412 may or may not contact the wall ofthe artery during PEF therapy. The electrode 412 preferably isfabricated from platinum or another material that exhibits relativelyhigh conductivity and radiopacity.

The system 400 further comprises the previously described externalground pad 150, which may be coupled to the PEF generator 100 (FIG. 4)and electrically coupled to the skin S of the patient along the exteriorof the patient (e.g., to the patient's flank, back or thigh). As withprevious embodiments, the ground pad 150 optionally may be positionedsubstantially directly lateral to the monopolar electrode 412 to directthe PEF therapy along the patient's vasculature (e.g., the renal arteryRA) and/or through the patient's kidney. Such lateral positioning of theground pad also may provide a relatively uniform distribution of energyabout the circumference of the patient's renal artery RA.

FIG. 6B illustrates an alternative embodiment of system 400 comprising aplurality of the electrodes 412 coupled to the shaft of the catheter410. Providing a plurality of the electrodes may facilitate themonopolar PEF treatment at multiple intravascular locations withoutnecessitating repositioning of the catheter 410. The electrodes may beselectively energized as monopolar (i.e., active) electrodes in anyorder or combination as desired. In one example, the electrodes may beindividually activated in sequence from proximal to distal. In anotherexample, the electrodes may be individually activated in sequence fromdistal to proximal. In another example, some electrodes are notactivated at all. In yet another example, one or more electrodes areactivated in combination with one or more other electrodes. In stillanother example, the electrodes are activated in a pre-determinedsequence or in a random sequence. Additional activation protocols willbe apparent to those of skill in the art.

In addition or as an alternative to their use in monopolar treatment,the plurality of the electrodes 412 of FIG. 6B optionally may be usedfor a bipolar PEF treatment. Such a bipolar PEF treatment may bedelivered across any pair or pairs of the electrodes 412, as desired. Acombination bipolar and monopolar PEF treatment may be more effectivethan stand-alone bipolar and/or stand-alone monopolar treatment for somepatients or for some indications.

Referring to FIGS. 7A-7D, embodiments of the intravascular monopolar PEFsystem 400 optionally may comprise one or more centering elements forcentering the monopolar electrode(s) within the patient's vasculature.The centering element(s) may be partially expanded such that theypartially center the monopolar electrode(s) within the vessel, or may befully expanded as in FIGS. 7A-7D, such that they substantially fullycenter the electrode(s) within the vessel. The centering elements 420may, for example, comprise inflatable balloons and/or expandable wirebaskets or cages.

The centering element optionally may comprise an impedance-alteringelement configured to alter impedance within the patient's vasculatureto better direct an applied electric field across the vessel wall totarget neural fibers. When the centering element is a balloon, it maytemporarily block blood flow and thereby alter the impedance within thepatient's vessel. Additionally or alternatively, the centering elementmay comprise the monopolar electrode. In one embodiment, a ballooncentering element comprises a conductive exterior and/or is fabricatedfrom a conductive polymer and is used as the monopolar electrode.

In FIG. 7A, the PEF system 400 comprises an expandable centering element420 coupled to the catheter 410. The element 420 is configured fordelivery and retrieval from a treatment site in a reduced profiledelivery configuration, and for expansion at the treatment site to thedeployed configuration of FIG. 7A. With the centering element in thefully expanded, deployed configuration of FIG. 7A, the monopolarelectrode(s) 412 are substantially centered within the vessel during thePEF therapy.

In the embodiment of FIG. 7A, the system 400 comprises a unitarymonopolar electrode 412 positioned along the shaft of the catheter 410proximal of the centering element 420. The centering element isaccordingly positioned between the monopolar electrode 412 and theground pad 150 in this embodiment. In the embodiment of FIG. 7B, themonopolar electrode 412 is positioned distal of the centering elementsuch that the centering element is not positioned between the monopolarelectrode and the ground pad. In the embodiment of FIG. 7C, themonopolar electrode 412 is positioned in line with the centering element420 along the shaft of the catheter 410. In the embodiment of FIG. 7D,the monopolar electrode 412 is positioned between first and secondcentering elements 420 a and 420 b, respectively. As will be apparent,additional monopolar and/or bipolar electrodes may be provided with anyof the embodiments of the system 400 of FIGS. 7A-7D at any desiredposition(s) along the catheter 410. Furthermore, one or more electrodesmay be coupled to the centering element(s) 420 such that the electrodescontact the wall of the patient's vasculature during delivery of the PEFtherapy.

As discussed previously, it is expected that the monopolar PEF therapy,whether delivered extravascularly, intravascularly,intra-to-extravascularly or a combination thereof, may effectuate thefollowing: irreversible electroporation or electrofusion; necrosisand/or inducement of apoptosis; alteration of gene expression; actionpotential blockade or attenuation; changes in cytokine up-regulation;and other conditions in target neural fibers. In some patients, whensuch neuromodulatory methods and apparatus are applied to renal nervesand/or other neural fibers that contribute to renal neural functions,applicants believe that the neuromodulatory effects induced by theneuromodulation might result in at least partial denervation of thepatient's kidney(s). This may result in increased urine output,decreased plasma renin levels, decreased tissue (e.g., kidney) and/orurine catecholamines (e.g., norepinephrine), increased urinary sodiumexcretion, and/or controlled blood pressure. Furthermore, applicantsbelieve that these or other changes might prevent or treat congestiveheart failure, hypertension, myocardial infarction, renal disease,contrast nephropathy, other renal system diseases, and/or other renal orcardio-renal anomalies for a period of months (e.g., potentially up tosix months or more).

The methods and apparatus described herein could be used to modulateefferent or afferent nerve signals, as well as combinations of efferentand afferent nerve signals. Neuromodulation in accordance with thepresent invention preferably is achieved without completely physicallysevering, i.e., without fully cutting, the target neural fibers.However, it should be understood that such neuromodulation mayfunctionally sever the neural fibers even though the fibers may not becompletely physically severed. Apparatus and methods described hereinillustratively are configured for percutaneous use. Such percutaneoususe may be endoluminal, laparoscopic, a combination thereof, etc.

The apparatus described herein additionally may be used to quantify theefficacy, extent or cell selectivity of PEF therapy to monitor and/orcontrol the therapy. When a pulsed electric field initiateselectroporation, the impedance of the electroporated tissue begins todecrease and the conductivity of the tissue begins to increase. If theelectroporation is reversible, the tissue electrical parameters willreturn or approximate baseline values upon cessation of the PEF.However, if the electroporation is irreversible, the changes in tissueparameters will persist after termination of the PEF. These phenomenamay be utilized to monitor both the onset and the effects of PEFtherapy. For example, electroporation may be monitored directly using,for example, conductivity measurements or impedance measurements, suchas Electrical Impedance Tomography (“EIT”) and/or other electricalimpedance/conductivity measurements like an electrical impedance orconductivity index. Such electroporation monitoring data optionally maybe used in one or more feedback loops to control delivery of PEFtherapy.

In order to collect the desired monitoring data, additional monitoringelectrodes optionally may be provided in proximity to the monitoredtissue. The distance between such monitoring electrodes preferably wouldbe specified prior to therapy delivery and used to determineconductivity from impedance or conductance measurements. For thepurposes of the present invention, the imaginary part of impedance maybe ignored such that impedance is defined as voltage divided by current,while conductance may be defined as the inverse of impedance (i.e.,current divided by voltage), and conductivity may be defined asconductance per unit distance. Applicants have previously describedmethods and apparatus for monitoring PEF therapy and have providedillustrative PEF waveforms, for example, in co-pending U.S. patentapplication Ser. No. 11/233,814, filed Sep. 23, 2005, which has beenincorporated herein by reference in its entirety.

With reference now to FIG. 8, a method for multi-location, monopolarrenal neuromodulation is described. In this embodiment, monopolar renalneuromodulation may be performed at a plurality of treatment sites Tpositioned along the length of renal artery RA. Such multi-locationtreatment may be achieved utilizing one or more monopolar electrodespositioned intravascularly, intra-to-extravascularly, extravascularly,etc. In FIG. 8, the multi-location treatment is performed withsubstantially uniform circumferential energy delivery about the renalartery RA. However, it should be understood that non-uniformcircumferential energy delivery alternatively may be utilized. Forexample, in some embodiments the monopolar electrode(s) may contact thevessel wall and may preferentially deliver energy to target neuralfibers located in proximity to the contacted side of the wall.

In one embodiment, the catheter 410 of the PEF system 400 of FIG. 6A isrepositioned along the renal artery RA for repeat therapy with electrode412 at multiple locations within the renal artery. In anotherembodiment, the multiple electrodes 412 of the PEF system 400 of FIG. 6Bare utilized to achieve renal neuromodulation at multiple treatmentsites T without repositioning the catheter 410. Such multi-locationtreatment may be achieved, for example, by simultaneously activatingmultiple electrodes 412 along the length of catheter 410, or bysequentially activating a series of electrodes. All or a subset of themonopolar electrodes of the embodiment of FIG. 6B may be activated toachieve desired renal neuromodulation.

FIG. 9 schematically illustrates an embodiment of a monopolar PEF system500 having a plurality of monopolar electrodes that may be expanded intocontact with the vessel wall. The PEF system 500 comprises a catheter510 having an expandable distal cage or basket 520 formed from aplurality of circumferential struts or members. A plurality ofelectrodes 524 are formed along the members 522 of the basket 520. Eachmember of the basket illustratively comprises a monopolar electrodeconfigured to contact a wall of the renal artery RA or another desiredblood vessel.

The basket 520 may be fabricated, for example, from a plurality ofshape-memory wires or ribbons, such as Nitinol, spring steel or elgiloywires or ribbons, which form the basket members 522. When the basketmembers comprise ribbons, the ribbons may be moved such that a surfacearea contacting the vessel wall is increased. The basket members 522 arecoupled to the catheter 510 at the proximal and the distal connections526 a and 526 b, respectively. In such a configuration, the basket maybe collapsed for delivery within a delivery sheath and may self-expandinto contact with the wall of the artery upon removal from the sheath.The proximal and/or the distal connection 526 optionally may beconfigured to translate along the shaft of the catheter 510 for aspecified or unspecified distance in order to facilitate the expansionand collapse of the basket.

The basket 520 alternatively may be formed from a slotted and/or alaser-cut hypotube. In such a configuration, the catheter 510 may, forexample, comprise an inner and an outer shaft that are moveable relativeto one another. The distal connection 526 b of the basket 520 may becoupled to the inner shaft, and the proximal connection 526 a of thebasket may be coupled to the outer shaft. The basket 520 may be expandedfrom a collapsed delivery configuration to the deployed configuration ofFIG. 9 by approximating the inner and the outer shafts of the catheter510, thereby approximating the proximal and distal connections 526 ofthe basket and expanding the basket. Likewise, the basket may becollapsed by separating the inner and outer shafts of the catheter.

As seen in FIG. 9, individual electrodes may be arranged along thebasket struts or members 522. In one embodiment, the struts are formedfrom a conductive material coated with a dielectric material, and theelectrodes 524 are formed by removing regions of the dielectric coating.The insulation optionally may be removed only along radially outersurfaces of the members such that the electrodes 524 remain insulated ontheir radially interior surfaces; it is expected that this will directthe current flow outward into the vessel wall.

Other optional fabrication techniques include affixing the electrodes tothe inside surfaces and/or outside surfaces of the basket struts, orembedding the electrodes within the struts. The electrode(s) placedalong each strut or member may comprise individual electrodes, a commonbut segmented electrode, or a common and continuous electrode.Individual electrodes or groups of electrodes may be configured toprovide a bipolar signal, or all or a subset of the electrodes may beactuated together in conjunction with an external patient ground formonopolar use.

One advantage of having electrodes 524 contact the vessel wall as shownin the embodiment of FIG. 9 is that it may reduce the need for aninsulating element, such as an expandable balloon, to achieve renaldenervation or other neuromodulation. However, it should be understoodthat such an insulating element may be provided and, for example,expanded within the basket. Furthermore, having the electrodes contactthe wall may provide improved field geometry, i.e., may provide anelectric field more aligned with the longitudinal axis of the vessel.Such contacting electrodes also may facilitate stimulation of the renalnerves before, during or after neuromodulation to better position thecatheter 510 before treatment or for monitoring the effectiveness oftreatment. Furtherstill, wall contact may facilitate multi-locationtherapy, as in FIG. 8.

FIG. 10 shows another PEF system 600 having one or more monopolarelectrodes that contact the vessel wall. In this embodiment, the PEFsystem 600 comprises a catheter 610 with an optional expandablecentering element 620 (e.g., an optional expandable balloon). The PEFsystem 600 further comprises an expandable helical electrode 630configured for delivery in a reduced profile configuration through aguidewire lumen 612 of the catheter 610. The helical electrode 630 may,for example, be fabricated from a self-expanding material, such asNitinol, elgiloy or spring steel.

As seen in FIG. 10, after positioning the catheter 620 in a targetvessel (e.g. renal artery RA), the optional centering element 620 may beexpanded, e.g., inflated until it contacts the wall of the vessel tohold the catheter at a desired location within the vessel and/or toinsulate or increase the impedance of the interior of the vessel. Thehelical electrode 630 is pushed through the lumen 612 until the helicalelectrode extends beyond the catheter shaft; the electrode then expandsor otherwise moves into the helical configuration to physically contactthe vessel wall. A monopolar pulsed electric field then may be deliveredbetween the helical electrode 630 and external ground pad 150.

FIG. 11 illustrates a method for bilateral monopolar renalneuromodulation utilizing the apparatus of FIG. 6A. It should beunderstood that such bilateral monopolar renal neuromodulationalternatively may be achieved utilizing the extravascular apparatus ofFIG. 4 or any other of the foregoing intravascular apparatus,extravascular apparatus, intra-to-extravascular apparatus, orcombinations thereof. Bilateral renal neuromodulation may enhance thetherapeutic effect in some patients as compared to unilateral renalneuromodulation (i.e., renal neuromodulation performed on neural tissueinnervating a single kidney). For example, bilateral renalneuromodulation may further reduce clinical symptoms of CHF,hypertension, myocardial infarction, contrast nephropathy, renal diseaseand/or other cardio-renal diseases.

As seen in FIG. 11, the catheter 410 of the monopolar PEF system 400 ofFIG. 6A may be advanced over a guide wire G into position within thepatient's abdominal aorta AA such that the monopolar electrode 412 issubstantially in line with the patient's renal arteries RA. First andsecond ground pads 150 a and 150 b, respectively, are electricallycoupled to the patient's skin S substantially directly lateral to therenal arteries RA. Once the catheter is properly positioned for PEFtherapy, the guide wire G may be retracted from the treatment zone(e.g., may be removed from the patient or may be positioned moreproximally within the patient's aorta). A pulsed electric field then maybe delivered to the active monopolar electrode 412 from the PEFgenerator 100. The pulsed electric field propagates from the monopolarelectrode 412 to the ground pads 150 a and 150 b to achieve desiredbipolar renal neuromodulation.

Monopolar bilateral renal neuromodulation optionally may be performedsequentially by sequentially advancing a monopolar electrode within, orin proximity to, each renal artery RA for PEF therapy. Alternatively, asin the illustrative embodiment FIG. 12, the monopolar electrodes may bepositioned simultaneously within both renal arteries RA, but in otherembodiments the electrodes can be positioned extravascularly orintra-to-extravascularly with respect to both renal arteries. Monopolarbilateral PEF therapy then may proceed concurrently or sequentially tomodulate target neural fibers that contribute to both right and leftrenal function.

FIG. 12 illustrates one embodiment of a bilateral monopolar PEF system700 that comprises a catheter 710 having a first distal segment 720 awith a first monopolar electrode 730 a and a second distal segment 720 bwith a second monopolar electrode 730 b. As seen in FIG. 12, the firstdistal segment 720 a may be advanced within a first renal artery RA toposition the first monopolar electrode 730 a for monopolar therapy incombination with the first ground pad 150 a. Likewise, the second distalsegment 720 b may be advanced within a second renal artery RA toposition the second monopolar electrode 730 b for monopolar therapy incombination with the second ground pad 150 b. As discussed, thebilateral renal neuromodulation may be performed concurrently orsequentially.

Although preferred illustrative variations of the present invention aredescribed above, it will be apparent to those skilled in the art thatvarious changes and modifications may be made thereto without departingfrom the invention. For example, although the monopolar bilateralmethods and apparatus for renal neuromodulation of FIGS. 11 and 12illustratively utilize dual ground pads, it should be understood thatsuch monopolar bilateral renal neuromodulation alternatively may beperformed with a single ground pad. Furthermore, although theillustrative variations described herein generally deliver monopolarrenal neuromodulation from within or in proximity to a patient's renalartery, it should be understood that such neuromodulation additionallyor alternatively may be delivered from other locations within or inproximity to the patient's renal vasculature, such as within or inproximity to the patient's renal vein. It is intended in the appendedclaims to cover all such changes and modifications that fall within thetrue spirit and scope of the invention.

1-25. (canceled)
 26. A method, comprising: intravascularly positioning acatheter in a reduced profile delivery configuration at a treatment sitewithin a renal artery of a human patient and adjacent to renal nerves;at the treatment site, transforming an expandable member at a distalportion of the catheter between the reduced profile deliveryconfiguration and a treatment configuration, wherein, in the treatmentconfiguration, the expandable member is sized and shaped to place aplurality of electrodes arranged thereabout into apposition with aninner wall of the renal artery of the patient; selectively energizing afirst electrode group of the expandable member to deliver a bipolarenergy field to the renal nerves; and selectively energizing a secondelectrode group at the distal portion of the catheter to deliver aunipolar energy field to the renal nerves, wherein delivering thebipolar energy field and the unipolar energy field modulates neuralsignaling along the renal nerves.
 27. The method of claim 26 wherein thebipolar energy field is generated by two or more electrodes carried bythe expandable member.
 28. The method of claim 26 wherein the unipolarenergy field is generated between one or more electrodes carried by theexpandable member and a unipolar electrode carried by a shaft of thecatheter and positioned proximate to the expandable member.
 29. Themethod of claim 26 wherein the treatment site is a first treatment site,the bipolar energy field is a first bipolar energy field, and theunipolar energy field is a first unipolar energy field, and wherein themethod further comprises: at the first treatment site, transforming theexpandable member between the treatment configuration and the reducedprofile delivery configuration; distally repositioning the catheter to asecond treatment site different than the first treatment site; at thesecond treatment site, transforming the expandable member between thereduced profile delivery configuration and the treatment configuration,for a second treatment; selectively energizing the first electrode groupand delivering a second bipolar energy field to the renal nerves at thesecond treatment site; and selectively energizing the second electrodegroup and delivering a second unipolar energy field to the renal nervesat the second treatment site, wherein delivering the second bipolarenergy field and second unipolar energy field further modulates neuralsignaling along the renal nerves.
 30. The method of claim 26 wherein theexpandable member comprises a balloon, and wherein transforming theballoon between the reduced profile delivery configuration and thetreatment configuration comprises expanding the balloon such thatelectrodes arranged thereabout are placed into contact with the innerwall of the renal artery.
 31. The method of claim 30 wherein, when theballoon is in the treatment configuration, blood flow is occluded withinthe renal artery.
 32. The method of claim 26 wherein modulating neuralsignaling along the renal nerves results in a therapeutically beneficialreduction in blood pressure of the patient.
 33. The method of claim 26,further comprising monitoring a parameter of the catheter and/or tissuewithin the patient before and during delivery of the bipolar energyfield and the unipolar energy field.
 34. The method of claim 33, furthercomprising altering delivery of at least one of the bipolar energy fieldand the unipolar energy field in response to the monitored parameter.35. The method of claim 33 wherein monitoring a parameter comprisesmonitoring a thermal response of the tissue, and wherein the methodfurther comprises maintaining the desired thermal response of the tissueduring delivery of the bipolar energy field and the unipolar energyfield.
 36. The method of claim 26 wherein delivering the bipolar energyfield and the unipolar energy field to the renal nerves comprises atleast partially ablating one or more renal nerves of the patient. 37.The method of claim 26 wherein delivering the bipolar energy field andthe unipolar energy field to the renal nerves comprises thermallyaltering the renal nerves in a manner that reduces neural traffic to andfrom a kidney of the patient.
 38. A method for treating a hypertensivehuman patient, the method comprising: positioning an expandable memberof a renal denervation catheter at an intravascular location within arenal artery of a human patient and adjacent to neural fibersinnervating a kidney of the patient for a treatment, wherein thecatheter includes a plurality of first electrodes carried by theexpandable member and a second electrode carried by a shaft of thecatheter proximate the expandable member; transforming the expandablemember between a low-profile delivery state and an expanded treatmentstate, wherein, in the treatment state, the expandable member is sizedand shaped to place the first electrodes into contact with a wall of therenal artery; and ablating the neural fibers innervating the kidney viaradio frequency (RF) energy delivered in a bipolar fashion using thefirst electrodes and RF energy delivered in a unipolar fashion using thesecond electrode.
 39. The method of claim 38 wherein ablating the neuralfibers innervating the kidney using radio frequency (RF) energy resultsin a therapeutically beneficial reduction in blood pressure of thehypertensive patient.
 40. The method of claim 38 wherein ablating theneural fibers innervating the kidney via RF energy comprises ablatingthe neural fibers using a combination of (a) bipolar energy deliveryfrom the bipolar electrodes carried by the expandable member and (b)unipolar energy delivery from the unipolar electrode and one or more ofthe bipolar electrodes carried by the expandable member.
 41. The methodof claim 38 wherein positioning an expandable member of a renaldenervation catheter at an intravascular location within a renal arterycomprises positioning a balloon carrying the plurality of firstelectrodes within the renal artery of the patient.
 42. The method ofclaim 38, further comprising monitoring a parameter of the renaldenervation catheter and/or tissue within the patient before and duringdelivery of the RF energy and altering delivery of the RF energy inresponse to the monitored parameter.
 43. The method of claim 42 whereinmonitoring a parameter comprises monitoring temperature, power, and/orimpedance.
 44. The method of claim 38, further comprising removing therenal denervation catheter from the patient after ablating the neuralfibers.